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Sialoglycoproteomic network and target discovery for Alzheimer's disease

唾液酸糖蛋白质组网络和阿尔茨海默病的靶标发现

基本信息

批准号：
10734612
负责人：
LIAN LI
金额：
$ 78.37万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734612
关键词：
Address Affect Age Alzheimer&apos s Disease Alzheimer&apos s Disease Pathway Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease diagnostic Alzheimer&apos s disease risk Alzheimer’s disease biomarker Animal Model Area Autopsy Binding Biological Biological Markers Biology Blood Brain Carbon Cell surface Cellular biology Cerebrospinal Fluid Charge Clinical Couples DNA Sequence Alteration Data Dementia Development Disease Disease Progression Drug Targeting Early Diagnosis Early Intervention Enzymes Functional disorder Glycoproteins Health Homeostasis Human Immunoglobulins Intervention Knowledge Lectin Link Masks Mass Spectrum Analysis Mediating Metabolism Molecular Molecular Target Monitor Monosaccharides Mutation NRCAM gene Neuraminic Acids Neuraminidase Neurodegenerative Disorders Neurologic Pathogenesis Pathogenicity Pathway interactions Patients Post-Translational Protein Processing Prevention Process Protein Conformation Proteins Research Resolution Risk Factors Role Sampling Serum Sialic Acids Sialoglycoproteins Sialyltransferases Signal Transduction Site Source Specimen Study models System Systems Biology Testing Translational Research Validation biomarker development biomarker discovery brain dysfunction brain tissue case control disease prognosis effective therapy extracellular follow-up genome wide association study glycoproteomics human disease improved in vivo innovation insight mild cognitive impairment molecular recognition neuropathology novel novel marker protein folding sialic acid binding Ig-like lectin sialylation targeted treatment therapeutic development trafficking

项目摘要

Project Summary / Abstract Alzheimer's disease (AD) is a devastating dementia with no effective treatment, underscoring the critical need for better understanding the pathogenic mechanisms of this disease and uncovering new molecular vulnerabilities to target for therapy. This project addresses an important yet under-studied area of AD research and aims to discover sialylation-mediated disease processes and novel targets for early diagnosis and intervention. Protein sialylation is a post-translational modification that covalently attaches sialic acids (negatively charged nine-carbon monosaccharides also known as neuraminic acids) onto glycoproteins to generate sialoglycoproteins. Accumulating evidence indicates that sialic acids on sialoglycoproteins not only affect protein conformation, activity, and trafficking, but also serve as regulators of molecular and cellular interactions, acting as a biological mask for blocking molecular recognition and/or as a biological recognition signal for mediating interactions with specific proteins such as Siglecs (sialic-acid-binding immunoglobulin- type lectins). Protein sialylation is vital to brain function and homeostasis, as highlighted by the fact that genetic mutations in enzymes for catalyzing sialylation, desialylation, or sialic acid metabolism cause human diseases with brain dysfunction and neurological abnormalities. Furthermore, GWAS studies have identified Siglec-3 (also known as CD33) as a risk factor for AD, underlining the connection between dysregulated sialylation-mediated signaling and AD pathogenesis. However, very little is currently known about human brain sialoglycoproteome and its alterations in AD. The proposed project will address this knowledge gap and use an innovative, multi-faceted approach that combines sialoglycoproteomics, network biology, cell biology with translational research in human patient specimens to discover and study sialoglycoproteomic networks and sialylation-based molecular mechanisms and pathways underlying brain function in health and Alzheimer's disease. Furthermore, this project will perform large-scale high-resolution analyses of sialoglycoproteome changes in human AD and control cerebrospinal fluid, and blood serum samples to identify novel biomarkers for early diagnosis and monitoring disease progression. Findings from the proposed research will advance our understanding of AD pathogenesis and provide novel targets for AD diagnostic and therapeutic development.

项目摘要/摘要